The proposed study will capitalize on existing relationships between the University of Missouri, St. Louis, and the University of Cape Town, South Africa to characterize the neurobehavioral signatures of HIV in South African individuals infected with clade C virus. Clade C represents the most common form of HIV in the world and it remains a dominant strain in South Africa. Early studies suggested that individuals infected with clade C HIV may be less likely to develop cognitive impairments due to a natural variation in the dicysteine motif of the Tat protein (C31S) evident in clade C virus. In support of this hypothesis a recent study of individuals infected with clade C virus in Ethiopia exhibited minimal cognitive impairment. However, other biological studies suggest that clade C may infer neurovirulence and we have demonstrated that patients with clade C virus in India exhibit cognitive impairment relative to seronegative controls. Recently we have collected data from a small group of individuals infected with clade C in South Africa, and we also have obtained neuroimaging on HIV patients in South Africa. These preliminary studies suggest that cognition is likely negatively affected in clade C patients residing in South Africa. However, it is unknown whether the cognitive impairments identified in clade C are present in the context of the Tat protein defect, or whether they relate to other known virologic correlates of cognitive function such as proviral DNA level. Further, no study has addressed the neuroimaging signatures of clade C HIV. In the present study we will examine 200 treatment-naive, HIV-positive individuals with clade C HIV and 50 seronegative healthy controls matched on demographic characteristics and all recruited from South Africa. Laboratory, cognitive, and neuroimaging data will be obtained from the patients and controls. Neuroimaging will consist of diffusion tensor imaging (DTI) to derive novel metrics of quantified tractography developed by members of our team (Laidlaw) as well as traditional volumetric indices that are known neuriomaging signatures of impairment in clade B HIV. This will be the first transdisciplinary study of clade C neuropathogenesis and the results will significantly advance our understanding of viral clade diversity and cognitive outcomes associated with HIV. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the impact of clade C HIV on cognitive function among individuals in South Africa. We aim to demonstrate that cognitive impairment is present among individuals infected with clade C despite the presence a Tat protein defect. We also aim to demonstrate that these impairments correlate with proviral DNA levels and markers of novel neuroimaging signatures.